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Comparison of NRTI combinations ZDV/3TC vs TDF + FTC –Study 934 ABC/3TC vs TDF/FTC –HEAT Study –ACTG A5202 Study –ASSERT Study Comparison of TAF vs TDF –Studies GS-US-292-0104 and GS-US-292-0111
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GS-US-292-0104/0111 Design Objective –Non inferiority of E/C/F/TAF at W48: % HIV RNA < 50 c/mL by intention to treat, snapshot analysis (lower margin of the 95% CI for the difference = -12%) –Safety: serum creatinine, proteinuria, hip BMD, spine BMD E/C/F/TAF QD E/C/F/TDF placebo E/C/F/TDF QD E/C/F/TAF placebo Randomisation* 1 : 1 Double-blind Adults ARV-naïve HIV RNA > 1,000 c/mL Any CD4 cell count eGFR ≥ 50 mL/min * Randomisation was stratified by HIV RNA ( 100,000 c/mL), CD4 cell count at screening, and geographic region Studies GS-US-292-0104 and GS-US-292-0111: E/C/F/TAF QD vs E/C/F/TDF QD N = 867 N = 866 W96W144W48 Sax PE. Lancet 2015; 385:2606-15
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E/C/F/TAF N = 866 E/C/F/TDF N = 867 Median age, years3335 Female15% HIV RNA (log 10 c/mL), median4.58 HIV RNA > 100,000 c/mL23% CD4 cell count (/mm 3 ), median404406 CD4 < 200 per mm 3 13%14% eGFR (Cockroft-Gault), mL/min, median117114 Discontinuation by W48, n (%)45 (5%)71 (8%) For lack of efficacy23 For adverse event813 Lost to follow-up / Withdrew consent15 / 1218 / 16 Non-compliance21 Baseline characteristics and patient disposition GS-US-292-0104/0111 Studies GS-US-292-0104 and GS-US-292-0111: E/C/F/TAF QD vs E/C/F/TDF QD Sax PE. Lancet 2015; 385:2606-15
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–Intensive PK substudy : –E/C/F/TAF, N = 36 (PBMC substudy : 21/36) –E/C/F/TDF, N = 29 (PBMC substudy : 14/29) Sax PE. Lancet 2015; 385:2606-15 Plasma TFV and intracellular TFV-DP levels 06121824 Time (h) 5 10 100 500 E/C/F/TDF (N = 29) E/C/F/TAF (N = 36) E/C/F/TDF (N = 14) 0 5 10 15 20 E/C/F/TAF (N = 21) X 4.1 X Steady State TFV PK E/C/F/TDF N = 29 E/C/F/TAF N = 36 % reduction Mean AUC tau ng*h/mL (% CV)3,410 (25)297 (20)91 Mean plasma TFV concentration, ng/mL (SD) Intracellular TFV-DP TFV Exposure (µM*h), Geometric mean (95% CI) GS-US-292-0104/0111 Studies GS-US-292-0104 and GS-US-292-0111: E/C/F/TAF QD vs E/C/F/TDF QD
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Response to treatment at week 48 HIV RNA < 50 c/mL, ITT, snapshot analysis E/C/F/TAF E/C/F/TDF 25 50 100 75 92 90 % Adjusted difference (95% CI) = 2.0% (- 0.7 ; 4.7) 94 91 Primary analysis (Overall) < 100,000 0 800/ 866 784/ 867 87 89 86 89 93 91 By baseline HIV RNA (c/mL)By baseline CD4 count(/mm 3 ) > 100,000< 200≥ 200 610/ 672 171/ 196 174/ 195 629/ 670 96/ 112 104/ 117 703 /753 680/ 750 GS-US-292-0104/0111 Studies GS-US-292-0104 and GS-US-292-0111: E/C/F/TAF QD vs E/C/F/TDF QD Sax PE. Lancet 2015; 385:2606-15
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Response to treatment at week 48 Secondary endpoints 25 50 100 75 84.4 84.0 % Adjusted difference (95% CI) = 0.4% (- 3.0 ; 3.8) 98 97 HIV RNA < 20 c/mL, ITT, snapshot 0 93.0 92.3 97.5 97.0 763/ 789 781/ 801 Studies GS-US-292-0104 and GS-US-292-0111: E/C/F/TAF QD vs E/C/F/TDF QD Sax PE. Lancet 2015; 385:2606-15 Per-protocol Adjusted difference (95% CI) = 0.8% (- 1.0 ; 2.5) HIV RNA < 50 c/mL Missing=Failure analysis Missing=Excluded analysis Adjusted difference (95% CI) = 0.8% (- 1.8 ; -3.3) Adjusted difference (95% CI) = 0.5% (- 1.2 ; -2.1) GS-US-292-0104/0111 E/C/F/TAF E/C/F/TDF
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Criteria for resistance testing –2 consecutive HIV RNA > 50 c/mL (with the second ≥ 400 c/mL) after achieving 400 c/mL at W48 or last study visit E/C/F/TAF, N = 866E/C/F/TDF, N = 867 Analysed for the development of resistance16 (1.8%)19 (2.2%) Emergent primary genotypic resistance7 (0.8%)5 (0.6%) Emergent reverse transcriptase inhibitor resistance 75 M184V/I M184V/I + K65R 6161 3232 Emergent integrase inhibitor resistance53 T66A E92Q Q148R Q148R + T66I/A Q148R + E92Q N155H 120101120101 011010011010 Resistance data at week 48 GS-US-292-0104/0111 Studies GS-US-292-0104 and GS-US-292-0111: E/C/F/TAF QD vs E/C/F/TDF QD Sax PE. Lancet 2015; 385:2606-15
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E/C/F/TAFE/C/F/TDF Diarrhoea17%19% Nausea15%17% Headache14%13% Upper respiratory tract infection11%13% Nasopharyngitis9% Fatigue8% Cough8%7% Vomiting7%6% Arthralgia7%5% Back pain7% Insomnia7%6% Rash6% Pyrexia5% Dizziness5%4% Adverse events (all grades) occurring in ≥ 5% of patients in either group (W48) GS-US-292-0104/0111 Studies GS-US-292-0104 and GS-US-292-0111: E/C/F/TAF QD vs E/C/F/TDF QD Sax PE. Lancet 2015; 385:2606-15
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E/C/F/TAFE/C/F/TDF All adverse events8 (0.9%)13 (1.5% Adverse events related to study drug7 (0.8%)11 (1.3%) Adverse events leading to study drug discontinuation Death E/C/F/TAFE/C/F/TDF N23 Reason Embolic stroke Alochol poisoning Cardiac arrest Multiple drug overdose Myocardial infarction Related to study drugs00 Sax PE. Lancet 2015; 385:2606-15 GS-US-292-0104/0111 Studies GS-US-292-0104 and GS-US-292-0111: E/C/F/TAF QD vs E/C/F/TDF QD
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E/C/F/TAFE/C/F/TDF Any20% CK elevation7%6% LDL elevation (fasting)5%2% Hypercholesterolemia (fasting)2%1% Hematuria (quantitative)2% AST elevation2% Serum amylase elevation2%3% Neutropenia, < 1000 neutrophils/ L 2% ALT elevation1% Grade 3 or 4 laboratory abnormalities in ≥ 1% of patients in either group (W48) Discontinuation for renal event E/C/F/TAF = 0 E/C/F/TDF = 4 : renal failure = 2, decreased GFR = 1, nephropathy = 1 GS-US-292-0104/0111 Studies GS-US-292-0104 and GS-US-292-0111: E/C/F/TAF QD vs E/C/F/TDF QD Sax PE. Lancet 2015; 385:2606-15
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Mean (SD) change in eGFR (Cockcroft-Gault), mL/min, from baseline Studies GS-US-292-0104 and GS-US-292-0111: E/C/F/TAF QD vs E/C/F/TDF QD E/C/F/TAF E/C/F/TDF Sax PE. Lancet 2015; 385:2606-15 Cockroft-Gault 0 5 10 15 20 25 30 35 p < 0,001 26 12 CKD-EPI-serumCreatinine eGFR Equation 31 17 p < 0,001 GS-US-292-0104/0111 Patients with ≥ 25% Decrease in eGFR
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Changes in Quantitative proteinuria/creatininuria ratio at week 48 BaselineMedian % change at W48* E/C/F/TAFE/C/F/TDFE/C/F/TAFE/C/F/TDF Protein : creatinine (mg/g)44 -3+20 Albumin : creatinine (mg/g)55-5+7 Retinol binding protein : creatinine ( g/g) 6467+9+51 Beta2-microglobulin : creatinine ( g/g) 101103-32+24 * p<0.001 for all Studies GS-US-292-0104 and GS-US-292-0111: E/C/F/TAF QD vs E/C/F/TDF QD E/C/F/TAFE/C/F/TDF Subclinical tubulopathy ( > 2 confirmed abnormalities)01 (0.1) Serum creatinine (≥ 0.4 mg/dL increase)00 Hypophosphatemia (≥ 1 grade decrease)3 (0.3)4 (0.5) Normoglycemic glycosuria (≥ 1 grade increase urine glucose; serum glucose ≤ 100 mg/dL) 02 (0.2) Proteinuria (≥ 2 grade increase)2 (0.2) Renal laboratory abnormalities at week 48, n (%) Sax PE. Lancet 2015; 385:2606-15 GS-US-292-0104/0111
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Mean (SD) % change in Spine BMD through Week 48 845 850 797 816 784 773 ≥ 3% gain Spine BMD Change at W48 Gain or loss < 3% ≥ 3% loss E/C/F/TAF E/C/F/TDF GS-US-292-0104/0111 Studies GS-US-292-0104 and GS-US-292-0111: E/C/F/TAF QD vs E/C/F/TDF QD E/C/F/TAF E/C/F/TDF ‒ 1.30 p <0.001 ‒ 2.86 2448 Week 0 2 -2 -4 -6 0 Sax PE. Lancet 2015; 385:2606-15
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14 836 848 789 815 780 767 Mean (SD) % change in Hip BMD through Week 48 ≥ 3% gain Hip BMD Change at W48 Gain or loss < 3% ≥ 3% loss E/C/F/TAF E/C/F/TDF GS-US-292-0104/0111 Studies GS-US-292-0104 and GS-US-292-0111: E/C/F/TAF QD vs E/C/F/TDF QD ‒ 0.66 p <0.001 ‒ 2.95 2448 Week 0 E/C/F/TAF E/C/F/TDF 0 2 -2 -4 -6 Sax PE. Lancet 2015; 385:2606-15
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Fasting Lipids at Week 48 Patients initiating lipid-modifying medications: 3.6% E/C/F/TAF vs 2.9% E/C/F/TDF (p=0.42) E/C/F/TAF Baseline Week 48 E/C/F/TDF Baseline Week 48 GS-US-292-0104/0111 Studies GS-US-292-0104 and GS-US-292-0111: E/C/F/TAF QD vs E/C/F/TDF QD Total CholesterolLDLHDLTriglycerides Median Values (mg/dL) p <0.001 p <0.001 p <0.001 p=0.027 p=0.84 189 177 115 109 51 48 108 114 160 101 44 95 0 50 100 150 200 TC:HDL Ratio 3.7 3.6 0 1 2 3 4 5 Sax PE. Lancet 2015; 385:2606-15
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Summary of week 48 results –E/C/F/TAF QD is virologically non inferior to E/C/F/TDF QD –92% of patients treated with E/C/F/TAF achieved virologic suppression through week 48 –High and similar response rates, irrespective of baseline HIV RNA and CD4 cell count, age, sex, race –Low rates of virologic failure, with resistance emergence < 1% in both arms –CD4 response from baseline significantly higher with E/C/F/TAF –Discontinuation because of adverse events : 0.9 % vs 1.5 % Discontinuation due to renal events : 0 vs 4 –Common adverse events occurred at similar frequency in both arms –No case of proximal tubulopathy –Compared with E/C/F/TDF, E/C/F/TAF demonstrated Significantly smaller decreases in eGFR Significantly less proteinuria, albuminuria, and tubular proteinuria Significantly less impact on spine and hip BMD Greater increases in fasting lipids GS-US-292-0104/0111 Studies GS-US-292-0104 and GS-US-292-0111: E/C/F/TAF QD vs E/C/F/TDF QD Sax PE. Lancet 2015; 385:2606-15
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